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RESEARCH ARTICLE

The presence of the gadolinium-based

contrast agent depositions in the brain and

symptoms of gadolinium neurotoxicity - A

systematic review

Cyprian Olchowy1*, Kamil Cebulski2, Mateusz Łasecki1, Radosław Chaber3,

Anna Olchowy2, Krzysztof Kałwak4, Urszula Zaleska-Dorobisz1

1 Department of General and Pediatric Radiology, Wroclaw Medical University, Wrocław, Poland,

2 Radiology Students’ Scientific Club, Wrocław Medical University, Wroclaw, Poland Department of General

and Pediatric Radiology, Wroclaw Medical University, Wroclaw, Poland, 3 Division of Hematology, Cancer

Prevention and Propaedeutics of Rare Diseases, Faculty of Medicine, University of Rzeszow, Rzeszow,

Poland, 4 Department of Pediatric Hematology, Oncology and BMT, Wroclaw Medical University, Wrocław,

Poland

* [email protected]

Abstract

Background and purpose

Gadolinium based contrast agents (GBCAs) are widely used in magnetic resonance

imaging, but recently, high signal intensity in the cerebellum structures was reported after

repeated administrations of contrast- enhanced magnetic resonance images. The aim of

this systematic review was to investigate the association between increased signal inten-

sity in the dentate nucleus and globus pallidus in the brain and repeated administrations

of GBCAs. Additionally, we focused on possible short- and long-term consequences of

gadolinium use in those patients.

Methods

Systematic review of retrospective investigations in PubMed and Medline was performed in

July 2016. Primary outcomes included the presence of increased signal intensity within the

dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in patients fol-

lowing administrations of GBCAs. Two independent reviewers were responsible for search

and data extraction.

Results

25 publications satisfied inclusion criteria (19 magnetic resonance images analyses, 3 case

reports; 3 autopsy studies). Magnetic resonance images of 1247 patients with increased sig-

nal intensity on unenhanced T1-weighted MR images were analyzed as well as tissue speci-

mens from 27 patients. Signal intensity correlated positively with the exposure to GBCAs

and was greater after serial administrations of linear nonionic than cyclic contrast agents.

Gadolinium was detected in all tissue examinations.

PLOS ONE | DOI:10.1371/journal.pone.0171704 February 10, 2017 1 / 14

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OPENACCESS

Citation: Olchowy C, Cebulski K, Łasecki M, Chaber

R, Olchowy A, Kałwak K, et al. (2017) The presence

of the gadolinium-based contrast agent depositions

in the brain and symptoms of gadolinium

neurotoxicity - A systematic review. PLoS ONE 12

(2): e0171704. doi:10.1371/journal.pone.0171704

Editor: Subhra Mohapatra, University of South

Florida, UNITED STATES

Received: August 7, 2016

Accepted: January 23, 2017

Published: February 10, 2017

Copyright: © 2017 Olchowy et al. This is an open

access article distributed under the terms of the

Creative Commons Attribution License, which

permits unrestricted use, distribution, and

reproduction in any medium, provided the original

author and source are credited.

Data Availability Statement: All relevant data are

within the manuscript.

Funding: The authors received no specific funding

for this work.

Competing interests: The authors have declared

that no competing interests exist.

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http://creativecommons.org/licenses/by/4.0/

Conclusions

High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted

magnetic resonance images were associated with previous administration of GBCAs. Sig-

nal intensity correlated negatively with stability of contrast agents. Clinical significance of

gadolinium deposition in the brain remains unclear. There is a strong need for further

research to identify type of gadolinium deposited in the brain as well as to gather knowledge

about long-term consequences.

Introduction

Magnetic resonance imaging (MRI) is one of the fastest developing noninvasive diagnostic

modalities in medicine. It employs innovative techniques and the newest discoveries, which

are safe and effective, but even so it is difficult to avoid pitfalls especially regarding long-term

consequences. The safety of gadolinium is now the most frequently discussed topic. This rare

paramagnetic metal is widely used in diagnostic imaging due to its high magnetic moment

and relatively long magnetic relaxation time. High toxicity of free gadolinium was eliminated

by closing free Gd3+ions in organic chelates. [1] Gadolinium based contrast agents (GBCAs)

are widely used in medicine since 1988, after Magnevist (Bayer Healthcare Pharmaceuticals)

gained the U.S. Food and Drug Administration approval. In 2014 unfortunately, Kanda et al.

observed connection between previous gadolinium administrations and high signal intensity

in the dentate nucleus and globus pallidus in the human brain independent of renal function.

[2] This discovery has drawn attention to the safety of contrast enhanced MRI. The impact of

gadolinium on human health remains unknown, although efforts are made to understand the

mechanisms of gadolinium toxicity which can help to find therapeutic and preventive solu-

tions for patients presenting signs and symptoms of gadolinium accumulation.[3]

Aim of the review

To shed more light on recent controversies regarding the use of GBCAs for MRI, we per-

formed a systematic review of the current literature with the aim to investigate the association

between increased signal intensity in the dentate nucleus and globus pallidus in the brain of

patients with a history of GBCA administrations. Additionally, we focused on possible short-

and long-term consequences of gadolinium use.

Search strategy

This study was done according to the guidelines of systematic reviews PRISMA. [4] We per-

formed a systematic search of PubMed and Medline databases for studies on MRI of the brain,

which assessed signal intensity of the dentate nucleus and globus pallidus performed in patients

following MRI examinations with GBCAs. The search was carried out in July 2016. The search

terms were gadolinium AND (dentate nucleus OR globus pallidus) and their combinations.

Additionally, we supplemented the electronic searches by hand searching the bibliographies of

relevant articles. Titles and abstracts were screened by two authors in order to exclude dupli-

cates and articles that did not meet the inclusion criteria. All other studies were retrieved for

full-text assessment performed by two researchers. Any discrepancies between the two review-

ers were resolved by consensus, with a third reviewer consulted when necessary.

Gadolinium and its deposition in the brain


Inclusion and exclusion criteria

Original studies, which investigated signal intensity in dentate nucleus and globus pallidus

examined in patients who had undergone repeated GBCA-enhanced magnetic resonance

(MR) were included in the analysis. We excluded studies with patients, in whom increased signal

intensity in those areas of the brain may have appeared due to other reason than gadolinium depo-

sition such as underlying Wilson disease, Rendu-Osler-Weber disease, manganese toxicity, calcifi-

cation, neurofibromatosis, or a history of total parenteral nutrition. Studies including patients

having hepatic or renal dysfunction as well as cases reports were analyzed for information about

side effects and toxicity related to gadolinium depositions in the brain. Letters, replies, editorials,

review articles, conference abstracts and animal studies were excluded.

Results

The electronic search strategy identified 54 publications; three additional papers were retrieved

by hand-search. Of this number, 25 studies satisfied all inclusion and exclusion criteria for this

review. Among included studies, there were 19 original studies of magnetic resonance images,

3 case reports, and 3 autopsy studies. In total, 1247 patients with increased signal intensity on

unenhanced T1-weighted MR images as well as tissue specimens from 27 patients were ana-

lyzed. All the studies included into analysis were available and written in English. Process of

study inclusion and exclusion is presented in Fig 1. Table 1 includes the list of analyzed publi-

cations with a summary of main findings.

Association between increased signal intensity in the deep cerebellar

nuclei and previous administrations of GBCAs

Gadolinium is a heavy metal with unique paramagnetic properties. Due to seven unpaired

electrons, it has the best relativity of the other lanthanide ions. Gadolinium(III) ions (GD3+)

are toxic, but bound to a ligand, they can remain chelated in the body and are excreted intact.

[1] The list of available GBCAs is presented in Table 2.

Fig 1. Flow Diagram based on PRISMA Statement [4].

doi:10.1371/journal.pone.0171704.g001



Table 1. Publications included in the systematic review.

Study Study groups Administrations of

GBCA

Contrast agent Remarks

Original studies

1 Adin et al.

2015 [42]

• Control = 54

• Increased SI = 103

• 0

• 2–60; median 18

Predominance of

gadopentetate dimeglumine

(Magnevist)

No significant difference in SI between

Magnevist and non-Magnevist group

2 Cao et al I

2016 [37]

• On hemodialysis = 25

• Control on hemodialysis = 13

• Near-normal renal function = 25

• Control near normal renal

function = 13

• 1.8 ± 1

• 0

• 1.8 ± 1

• 0

linear GBCA The percentage of patients with increased SI

in DN post-GBCA was significantly greater in

relation to pre-GBCA only in the group on

hemodialysis.

3 Cao et al II

2016 [10]

• Gadobutrol group = 25

• Gadopentetate

dimeglumine = 25

• 7.8 ± 2.4 (6–16)

• 12.1 ± 5.2 (6–23)

gadobutrol and


Significant increase in SI in gadopentetate

dimeglumine group and insignificant in

gadobutrol group.

4 Errante 2014

[30]

• MS group = 38

• Brain metastases group = 37

• 2–14

• 2–21

gadodiamide (Omniscan) DNP were significantly higher between the

first and the last scan in both study groups in

patient with 6 or more examinations.

5 Flood 2016

[25]

• GBCA-naive control

subjects = 57

• GBCA-exposed patients = 30

• Pre- and post-GBCA

comparison = 16

• 0

• 5.9 ± 2.7

• 5.8 ± 2.1


(Magnevist)

SI in DN was significantly higher in the

GBCA-exposed group than the GBCA-naive

group.

6 Hu 2016 [19] • Control group = 21

• GBCA group = 21

• 0

• 5–37


(Magnevist)

Significant increase in the ND-to- corpus

callosum genu ratio and the GP-to- corpus

callosum genu ratio between the first and

most recent GBCA exam.

7 Kanda 2014

[2]

• contrast-enhanced MR

subgroup = 19

• unenhanced MR subgroup = 16

• 7.1 (6–12)

• 0


(Magnevist)

gadodiamide (Omniscan)

DNP and GPT ratio was correlated with the

number of previous contrast-enhanced MR

scan.

8 Kanda 2015

[9]

• Magnevist group = 23

• ProHance group = 36

• Both agenst = 14

• Control = 54

• median 2; max 11

• median 2; max 15

• median 2; max 5

• 0


(Magnevist)

gadoteridol (ProHance)

Only the DN-to-cerebellum ratio was

significantly associated with linear GBCA.

9 Kromrey 2016

[18]

• Gadobutrol group = 271

• Control group = 116

• 1

• 0

gadobutrol After 5-year follow-up, no significant

differences in SI were observed between

gadobutrol group and controls as well as

between baseline and follow-up

measurement.

10 Quattrocchi

2015 [14]

• group A = 10

• group B = 28

• group C = 8

• 1

• 1–5

• >6

gadodiamide A significant increase of DNP was between

the first and the last MRI in group C.

11 Radbruch I

2015 [12]

study group = 30 7.3 ± 3.1 gadobutrol No SI increase in the DN and GP was found

after serial applications gadobutrol.

12 Radbruch II

2015 [3]

• Magnevist group = 50

• Dotarem group = 50

• 7.32 ± 1.83

• 7.06 ± 1.20


(Magnevist), gadoterate

meglumine (Dotarem)

In the linear GBCA group, the mean

difference in SI of DNP between the last and

first examinations was significantly larger

than 0, while in the macrocyclic GBCA group

was not significant.

13 Ramalho I

2015 [17]

• Omniscan group = 23

• MultiHance group = 46

• 5.0 ± 2.4 (3–11)

• 4.6 ± 2.1 (3–11)


gadobenate dimeglumine

(MultiHance)

GPT and DN-to- middle cerebellar peduncle

ratio increased significantly over time with

multiple administrations of a linear nonionic

GBCA (gadodiamide) but did not increase

with serial applications of a linear ionic GBCA

(gadobenate dimeglumine).

14 Ramalho II

2016 [21]

• gadobenate dimeglumine = 44

• previous gadodiamide and

current gadobenate

dimeglumine = 18

• 4.5 ± 2.0 (3–11)

• 5.9 ± 2.7 (3–11)

• 5.5 ± 1.9 (3–10)


gadobenate dimeglumine

(MultiHance)

Significant increase in DN-to- middle

cerebellar peduncle ratio appeared after

gadodiamide injections. It was insignificantly

higher in the group receiving both GBCAs.

(Continued )



Increased signal intensity within the dentate nucleus and globus pallidus on unenhanced

T1-weighted MR images was observed by many radiologists, but its association with gadolin-

ium was not obvious [5–7]. Only in 2013, Kanda et al. noticed the important connection

Table 1. (Continued)

Study Study groups Administrations of

GBCA

Contrast agent Remarks

15 Ramalho II

2016 [44]

T1-weighted spin-echo and 3D

MPRAGE = 18

4.78 ± 2.51 (2–10) gadodiamide (Omniscan) The differences in DN-to- middle cerebellar

peduncle ratio between the 2 sequences for

both baseline and last examination were

statistically significant, but the change in ratio

with time was not.

16 Stojanov

2015 [31]

relapsing-remitting MS group = 58 4.74±0.72 (4–6) gadobutrol (Gadovist) DNP, but not GPT, showed a significant

correlation with the number of administered

doses of GBCA.

17 Tanaka 2016

[45]

• MS group = 21

• neuromyelitis optica spectrum

disorder group = 6

at least 10 linear Number of GBCA doses correlated positively

with signal intensity increase in 81% of MS

patients and in 33.3% of NMOsd patients.

18 Tedeschi

2016 [15]

relapsing-remitting MS group = 74 6.0 ± 3.8 (1–15) gadopentetate

dimeglumine,gadobutrol

Previous gadolinium administrations correlate

with DN T1 relaxometry and are linked to

linear gadolinium chelates.

19 Weberling

2015 [11]

study group = 50 7.7 ± 3.2 (5/15) gadobenate dimeglumine The DNP and DN-to-cerebrospinal fluid ratio

difference between the first and the last MRI

was significantly larger than 0.

Case reports

20 Barbieri 2016

[38]

3 cases patients with impaired

renal function and vascular

calcification; two of them had

NSF.

Gadoteridol, Gadodiamide Increased SI within DN and GP after

exposure to relatively low doses of linear

GBCAs

21 Roberts 2016

[24]

A patient with a clival chordoma. gadopentetate dimeglumine

(Magnevist)

Subtle hyperintensity within DN appeared

after 4 doses of MRI contrast and after sixth

dose hyperintensity was noted within both DN

and GP bilaterally.

22 Miller 2015

[46]

A pediatric patient. 35 Linear GBCA Progressive increases were the most evident

in DN, DP, and the thalamus.

Autopsy examinations

23 McDonald

2015 [20]

• GBCA group = 13

• Control group = 10

At least 4 gadodiamide DN was associated with the greatest dose-

dependent change in T1-weighted signal

intensity, whereas the pons demonstrated the

lowest overall absolute change in

T1-weighted signal intensity with gadolinium.

All patients exposed to multiple doses of a

GBCA had elevated levels of elemental

gadolinium in the four prescribed

neuroanatomic regions.

24 Kanda 2015

[27]

• GBCA group = 5

• Non-GBCA group = 5

At least 2 • gadopentetate

dimeglumine (Magnevist)

• gadodiamide (Omniscan)

• gadoteridol (ProHance)

Gadolinium was detected in all specimens in

the GBCA group and in some specimens in

the non-GBCA group; however, the

gadolinium concentration was significantly

higher in the GBCA group in each region.

25 Murata 2016

[28]

• gadoteridol group = 5

• gadobutrol group = 2

• gadobenate group = 1

• gadoxetate group = 1

• control group = 9

• gadoteridol (ProHance)

• gadobutrol (Gadovist)

• gadobenate (MultiHance)

• gadoxetate (Eovist)

Gadolinium deposition in normal brain and

bone tissue occurred with macrocyclic and

linear GBCAs in patients with normal renal

function.

Legend: SI, signal intensity; GBCA, gadolinium based contrast agent; DN, dentate nucleus; GB, globus pallidus; DNP, dentate nucleus-to-pons ration; GPT,

globus pallidus-to-thalamus ratio; MS, multiple sclerosis; NMOsd, neuromyelitis optica spectrum disorder group

doi:10.1371/journal.pone.0171704.t001



between changes visible on MRI scans and a history of multiple administrations of gadolin-

ium-based contrast material in patients with normal renal function. This research team

selected 19 patients who had undergone at least 6 contrast- enhanced MR examinations with

gadopentetate dimeglutamine (Magnevist) or gadodiamide (Omniscan) and 16 patients who

had at least 6 MR scans without contrast administration. Analysis of the data revealed a posi-

tive correlation between the number of previous gadolinium-based contrast material adminis-

trations and both the dentate nucleus-to-pons ratio and globus pallidus-to-thalamus ratio. [2]

Since this discovery, scientists from around the world began the race to provide more informa-

tion about association between gadolinium and signal intensity changes in the brain.

Different molecule structure due to bonding gadolinium to various ligands results in differ-

ences in physicochemical properties. In linear agents, Gd3+ is combined with open-chain

ligands, while in macrocyclic agents, the gadolinium ion is caged inside the cavity of organic

structure, which resembles a ring. [8] The structural difference between macrocyclic and linear

open-chain chelates mainly has an impact on the stability of the gadolinium chelate. Kanda’s

team aimed to compare the effect of administration of linear and macrocyclic gadolinium che-

lates. In the study group, hyperintensity in the dentate nucleus was found in 9 patients, out of

which 7 were given only linear chelate GBCA. The dentate nucleus-to-cerebellum ratio was

significantly associated with linear GBCAs. [9] Similar approach was used by Cao et al. who

compared two groups of patients: those who received gadobutrol (macrocyclic GBCA) with

those who received gadopentetate dimeglumine (linear GBCA). In gadopentetate dimeglumine

group, signal intensity measured in dentate nucleus increased significantly after six administra-

tions, while in gadobutrol group signal increase was not significant. [10] Other researchers also

reported no signal intensity increase in the dentate nucleus and globus pallidus after administra-

tion of macrocyclic GBCAs and significant signal increase after repeated administration of lin-

ear GBCAs in cancer patients. [11–14] Tedeschi linked changes in T1 relaxometry of dentate

nuclei observed in patients with relapsing-remitting multiple sclerosis to the number of previ-

ous GBCA administrations. T1-hyperintensity was highly significant for linear GBCA. [15]

Transmetalation of gadolinium chelates and the rate of the gadolinium ions release from

chelates in the presence of Zn2+ at pH 7.4 decreases relaxation rates. On this basis, 3 classes of

gadolinium contrast agents were determined using a long-term index which is equal to the

ratio of the paramagnetic relaxation rates after 50 h. [8,16] Macrocyclic chelates with very high

kinetic inertia stability have a long-term index exceeding 0.95, ionic linear open-chain chelates,

which have moderate kinetic inertia, have long-term index ranging from 0.49 to 0.85 and non-

ionic linear open-chain chelates characterized by poor kinetic stability and the highest degree

of dechelation have long-term index below 0.3. [8] Clinical comparison between two types of

linear GBCAs (ionic and non-ionic) was conducted by Ramalho et al. The study protocol was

based on comparison of signal intensity in globus pallidus and dentate nucleus between linear

nonionic gadodiamide (Omniscan) and linear ionic gadobenate dimeglumine (MultiHance).

After average of 5 injections of gadolinium based contrast, signal intensity ratios based on

Table 2. GBCAs approved for clinical use.

Nonionic Linear) Ionic Linear

• Omniscan (gadodiamide)

• OptiMARK (gadoversetamide

• Ablavar (gadofosveset trisodium)

• Eovist (gadoxetate disodium)

• Magnevist (gadopentetate dimeglumine)

• MultiHance (gadobenate dimeglumine)

Nonionic macrocyclic Ionic macrocyclic

• ProHance (gadoteridol)

• Gadavist (gadobutrol)

• Dotarem (gadoterate meglumine)

doi:10.1371/journal.pone.0171704.t002



measurement within dentate nucleus and middle cerebellar peduncle as well as globus pallidus

and thalamus increased significantly only in the group which received gadodiamide having the

worst long-term index. [17] Radbruch et al. reported that in case of macrocyclic GBCAs, the

difference in signal intensity in similar area was not significant even after average of 7 exami-

nations with gadoterate meglumine and gadobutrol. [12,13]

The long-term effect of a single injection of gadobutrol was examined based on SHIP data-

base conducted as a prospective population-based cohort study. After 5-year follow-up, no sig-

nificant difference in signal intensity was observed between gadobutrol group and controls as

well as between baseline and follow-up measurement. Signal intensity was measured within

thalamus, pallidum, pons, dentate nucleus as well as white matter and gray matter. The study

shows that gadobutrol does not lead to a measurable increase in signal intensity in neuronal

structures when applied even at a 1.5 times higher dose than generally required. [18] On the

contrary, Hu et al. reported visible changes as early as on the second examination carried out

with gadopentetate dimeglumine (ionic linear GBCA) in two pediatric patients. [19]

Investigators are interested in not only when the changes appear, but also whether they can

resolve. Usually, increased signal intensity within brain structures were reported after repeated

administrations of GBCAs of at least four times in case of linear contrast agents [12,20], but in

case of macrocyclic ones, exposure to six applications resulted in insignificant increase in sig-

nal intensity [10] Ramalho et al. showed that injections of a contrast agent characterized by

poor stability in the past results in signal increase even after using more stable contrasts in sub-

sequent examinations, which draws attention to potential potentiating effect of unstable

agents. [21] Birka et al. described a case of patient with nephrogenic systemic fibrosis; detect-

able amounts of gadolinium-phosphate deposits were found after 11 years post administration

of GBCA. [22] None of the authors reported decrease in signal intensity over time at the time

of writing our paper (by July 2016); however, during a revision of the manuscript, Radbruch

et al. reported a decrease in preexisting signal hyperintensity after changing from linear to

macrocyclic GBCA. It was suggested that some washout may exist. [23]

Many researchers reported similar changes within brain structures after gadolinium

enhanced MRI scans in pediatric patients. In the Hu’s et al. study, the changes, both in the den-

tate nucleus ratio and the globus pallidus ratio, were significant when compared between the

first and most recent GBCA examination. Investigators draw the attention to the fact that

hyperintensity either in the dentate nucleus or the globus pallidus was visually noticed within

the first 10 GBCA exams in all patients and in some patient even after 2 administrations of

contrast, which may indicate greater susceptibility in children. The correlation analysis

revealed no significant associations between signal intensity ratios and both the number of

examinations or the total volume of GBCA administered. [19] Roberts et al. described the case

of a girl with a clival chordoma in whom subtle hyperintensity appeared after fourth adminis-

tration of linear GBCA. [24] Flood et al. showed that signal intensity within the dentate

nucleus was significantly higher in the GBCA-exposed group than the GBCA-naive group.

Additionally, signal intensity comparison before and after repeated GBCA exposures showed

significant increase within dentate nucleus, while within the globus pallidus signal intensity

change remained insignificant. Additionally, the dentate nucleus-to-pons ratio was signifi-

cantly correlated with the total cumulative gadolinium dose, but insignificantly with the total

number of contrast-enhanced examinations. [25]

Evidence of gadolinium deposition in the brain

An increase of relative signal intensity in the dentate nucleus and the globus pallidus on unen-

hanced T1-weighted MR images following administration of GBCAs was linked to gadolinium



administration, but it was generally believed that the gadolinium chelates do not diffuse

through plasma membranes and do not cross the intact blood-brain barrier. [26]

The first report about gadolinium deposition in the brain was published in 2011. Sanyal

et al. analyzed tissues from an autopsy case with verified advanced nephrogenic systemic fibro-

sis and detected insoluble Gd-phosphate deposits in many organs including cerebellum; how-

ever, gadolinium depositions were found only in the perivascular glial cells. [26] McDolnald

et al. aimed to examine if signal hyperintensity within dentate nucleus and globus pallidus visi-

ble on T1-weighted MR images after repeated administrations of GBCAs is associated with

gadolinium deposition in neuronal tissues. They found elevated levels of elemental gadolinium

in the dentate nucleus, pons, globus pallidus, and thalamus in all patients exposed to multiple

doses of a linear GBCA, whereas control patients demonstrated undetectable levels of elemen-

tal gadolinium. Gadolinium concentration was strongly correlated with a cumulative gadolin-

ium dose. Examinations showed major gadolinium deposits in the endothelial walls and small

fraction of gadolinium deposited in the neural tissue interstitium, which suggests crossing

intact blood-brain barrier. [20] Due to technical difficulties, Kanda et al. analyzed smaller than

in McDonald’s study groups of deceased patients who had been given different GBCAs. The

gadolinium concentration in dentate nucleus, globus pallidus, cerebellar white matter, frontal

lobe cortex, and frontal lobe white matter was significantly higher in the GBCA group than

in non-GBCA group. Detection of gadolinium in the samples from non-GBCA group was

explained by contamination. [27] Murata et al. examined brain specimens in patients who had

received either linear of macrocyclic GBCAs. Among the tested agents, they found the lowest

gadolinium deposition ratio in brain tissue for the macrocyclic agent gadoteridol. [28] The

greatest limitation of brain autopsy studies is that they were not able to detect a specific form

of gadolinium.

In the view of current discussion about form of gadolinium deposition, the case reported by

Birka et al. brings additional information; though, it concerns a patient with nephrogenic sys-

temic fibrosis. The investigators were able to determine GdPO4 and gadoteridol from skin

specimens from a patient who received one administration of a linear GBCA (gadopentetate)

and one of a macrocyclic GBCA (gadoteridol) given 11 and 8 years before tissue examination.

Chelated forms of gadolinium were not found. [22]

Multiple sclerosis

The first observations of increased signal intensity in dentate nuclei were linked to the second-

ary progressive disease subtype of multiple sclerosis and to increased clinical disability, lesion

load, and brain atrophy. [5] Post-inflammatory changes are common in the brain of patients

suffering from multiple sclerosis and may resemble post-GBCA administration hyperintensity

of the dentate nucleus visible on unenhanced T1-weighted images. Diagnosis of multiple scle-

rosis as well as assessment of new lesions in the brain requires repeated contrast enhanced MR

examinations. Contrast enhancement on post-gadolinium T1-weighted imaging help to differ-

entiate acute and chronic lesions. [29] Errante et al. proved that signal increase in patients with

multiple sclerosis depends not only on underlying primary disease but also on the number of

previously performed gadolinium- enhanced MR examinations. According to their study, T1

signal intensity of the dentate nucleus in patients with at least 6 enhanced MRI scans was sig-

nificantly higher than those with less than 6 scans. [30] Stojanov et al. focus on examinations

performed in patients with relapsing-remitting multiple sclerosis who had undergo several

MR scans with gadobutrol, which is macrocyclic non-ionic GBCA, characterized by better sta-

bility than used by Errante et al. open chain gadodiamide. [31] Dentate nucleus-to-pons ratio

increased significantly after the last examination but the change of globus pallidus-to-thalamus



ratio was insignificant. Those results were obtained after average of 4.74 gadolinium-based

contrast administrations, which is quite early comparing with study groups excluding patients

with multiple sclerosis. Later, other researchers questioned Stojanov’s team outcomes because

of methodological limitations of the study. [11,32]

Renal insufficiency

As early as in 2006, Grobner informed about an association between magnetic resonance angi-

ography with gadopentetate dimeglumine as a contrast agent performed in patients with end-

stage renal disease and the development of nephrogenic systemic fibrosis. [33] Cabot et al.

reported a patient who died of nephrogenic systemic fibrosis. High levels of gadolinium were

found in all biopsied tissues; unfortunately, the brain tissue samples were then not collected

for autopsy. [34] A year later Sanyal et al., reported the presence of insoluble gadolinium-phos-

phate deposits also in the cerebellum; however, they were detected only in the perivascular

glial cells. [26]

One of the factors that contribute to the pathogenesis of nephrogenic systemic fibrosis is

the slow excretion of GBCAs in those patients allowing the lower stability gadolinium chelates

to dissociate and release toxic Gd3+. Additionally, gadodiamide can activate elevated fibroblast

growth and elevated levels of hyaluronan synthesis [35], which are responsible for clinical

symptoms of nephrogenic systemic fibrosis.

Patients with renal failure are exposed to prolonged effect of injected GBCAs because prompt

elimination though renal excretion is impossible in those patients. Impairment of renal function

is than a risk factor for deposition of gadolinium in tissues, including the brain. [36] As a result,

signal intensity in dentate nucleus on unenhanced T1-weighted images was greater in hemodialy-

sis patients than in patients with normal renal function after repeated administrations of GBCAs.

[37] Additionally, Barbieri et al. described three cases with impaired renal function and vascular

calcification, which presented with signal hyperintensity within the dentate nucleus and the globus

pallidus on unenhanced T1-weighted MR images after exposure to relatively low doses of linear

GBCAs. [38] Those reports suggest that impaired renal function accelerates the rate of gadolinium

accumulation in the brain.

Patients with a low estimated glomerular filtration rate are at higher risk of complications

related to GBCA administration than those with normal renal function. Currently, the Con-

trast Media Safety Committee of the European Society of Urogenital Radiology recommends

administering the smallest required amount of macrocyclic GBCAs, keeping at least weekly

break between injections and planning an additional dialysis session in patients on dialysis.

[39] Patients with impaired renal function should be carefully monitored, as they are prone to

known and unknown adverse reactions of gadolinium.

Brain irradiation

Radiation-related injury to the brain may result in calcifications, which are visible as an increase

of magnetic resonance signal intensity. [40] Post-radiation changes may give non-specific

hyperintense signal changes which are similar to many other conditions affecting the dentate

nuclei [41]; therefore, patients who had undergone brain irradiation are commonly excluded

from the studies examining the presence of hyperintense signal changes in relation to previous

gadolinium exposure. In our review, Adin’s at al. study included 129 patients with a history of

brain radiotherapy among other. Of that group, specific radiation exposures of the dentate

nuclei were confirmed for 108 subjects. Their analysis revealed that in the group with increased

signal intensity, the total exposure of the brain was lower than in the group without



hyperintensity, although the groups did not differ significantly. [42] Adin’s team report is in

line with Kanda et al. findings who reported that brain irradiation had no impact on signal

change. [2]

Neurotoxicity of GBCAs

Gadolinium chelates are considered safe because of their efficient renal excretion from the

body in an unchanged form. However, GBCAs have different stability, and therefore some

agents are more prone for dechelation than others are. Toxicity of gadolinium is associated

with similarity between gadolinium and calcium ions, but refers exceptionally to free ions.

Gd3+ can compete with Ca2+ and act as an inorganic blocker of voltage-gated calcium chan-

nels with all negative consequences in many sites of the human body. [1] Despite extensive

research, little is known about possible consequences of gadolinium brain depositions. Neither

mechanism responsible for collection of gadolinium in dentate nucleus and globus pallidus

nor the form of deposited gadolinium has been discovered.

The analysis of clinical events in 16 dialysis patients performed by Cao et al. allowed for

comparison of their frequency during a period of a month before with a month after each

exposure to linear GBCA. All neurological symptoms described during the 30 days after

GBCA administration such as migraine headache, loss of consciousness, memory loss, falling,

lightheadedness, and ataxia, occurred also before MRI with GBCA; therefore, they cannot be

related to gadolinium toxicity. [37] Barbieri et al. described three patients with impaired renal

function and vascular calcifications who presented with signal hyperintensity characteristic for

gadolinium brain depositions. All of them suffered from transient signs of neurological disor-

ders of undetermined cause, but the association of those symptoms with gadolinium toxicity

remains unclear. [38]

There are several patient advocacy groups, who gather people suffering from nephrogenic

systemic fibrosis and other symptoms related to GBCAs administration. Recently, a self-report

survey among patients, who attributed their symptoms to previous GBCA administrations,

was published. Respondents (n = 50) received intravenous gadolinium contrast with an aver-

age of 4.2 doses (range 1–23). Two-thirds of them experienced those symptoms immediately

following GBCA-enchanced examination. Bone/joint pain as well as head/neck problems such

as headache, vision change, and hearing change were mentioned the most frequently; they

occurred in more than 75% of questionnaires. About 60% of respondents complained about

dermatologic changes. [43] The study has a long list of limitations, but constitutes the first

description of symptoms, which may be related to gadolinium toxicity.

Technical considerations

The number of studies on the effect of using various GBCAs on the brain has been rapidly

increasing since the first report about association of previous repeated GBCAs and hyperinten-

sity of dentate nucleus and globus pallidus. [2] The level of knowledge increases, but when ana-

lyzing data, it seems that some researchers report incompatible findings affected by

unintended limitations. First, qualitative and quantitative signal-intensity measurement meth-

ods are used together in many studies. Many MRI protocols employed sequences such as

T1-weighted spin-echo [10,17,42], T1 MPRAGE [42], T1 FLAIR [30,42], T1-weighted 3D

MPRAGE [18,25] and FLASH [11] alone or in combination. Ramalho et al. concluded that

T1-weighted spin-echo and MPRAGE sequences should not be used interchangeably for quali-

tative or quantitative T1 signal-intensity analysis of the dentate nucleus in patients who

undergo several gadolinium-enhanced MR examinations as those methods result in statisti-

cally significant differences. [44]



Next, as those studies are retrospective in nature, it is sometimes difficult to retrieve informa-

tion or to collect proper study population. Studies present outcomes of different number of pre-

vious exposure to GBCAs administered at different time intervals; thus, heterogeneity of study

samples is a potential source of bias. Many of the reviewed studies included cancer patients who

had undergone radiation therapy [9–13], some included patients with impaired renal function

(estimated glomerular filtration rate<60 mL/min per 1.73 m2) [12] or increased liver serum

parameters [11–13] among others.

Conclusions

Literature review confirms that increased signal intensity in the dentate nucleus and globus

pallidus on unenhanced T1-weighted MR images is associated with previous administrations

of GBCAs, predominantly linear, and corresponds with the concentration of gadolinium in

the brain tissue.

Despite of rapidly growing number of published papers, the level of knowledge about gado-

linium depositions in the brain and their clinical significance remains insufficient; therefore, it

seems to be reasonable to choose the most stable types of GBCAs and avoid higher doses espe-

cially in children and young patients even with normal renal function.

There is a strong need for further research to shed light on the nature of gadolinium deposi-

tion in the brain, their effect on the brain tissue functioning and occurrence of long-lasting

adverse reaction. Multidisciplinary approach including participation of radiologists, neurolo-

gists, psychiatrists, and biologists who could evaluate the clinical significance of gadolinium

depositions in the brain in prospective projects encompassing pediatric patients are required.

Supporting information

S1 File. Prisma Checklist.

(DOC)

Author Contributions

Conceptualization: CO KC UZD.

Data curation: CO.

Formal analysis: CO KC.

Investigation: CO KC MŁ RC AO.

Methodology: CO UZD KK.

Project administration: CO UZD.

Supervision: RC KK UZD.

Validation: UZD.

Writing – original draft: CO KC MŁ AO.

Writing – review & editing: CO RC KK UZD.

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